A methylation clock model of mild SARS‐CoV‐2 infection provides insight into immune dysregulation

Abstract

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS‐CoV‐2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow‐up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation‐based machine learning models that distinguished samples from pre‐, during‐, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS‐CoV‐2 infection to the model‐defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS‐CoV‐2 epigenetic landscape we identify is antiprotective.

Epigenetic Control of Innate Immunity: Consequences of Acute Respiratory Virus Infection

“…This signature was characterized by a high proportion of hypomethylated regions in proximity to ISGs. Additionally, we found a large overlap with previously reported signatures associated with autoimmune diseases such as systemic lupus erythematosus or multiple sclerosis [78], indicating a potential dysregulation of the innate immune system.…”

“…The recent SARS-CoV-2 pandemic has led to multiple studies analyzing the epigenetic profile of the blood of individuals previously infected by SARS-CoV-2 ( Table 1 ). Using samples from a large cohort of young recruits as part of the COVID-19 Health Action Response for Marines (CHARM) study, we found that the DNA methylation profile in blood cells after infection is modified with respect to the pre-infection profile, and these changes persist for at least several weeks [ 78 ]. This signature was characterized by a high proportion of hypomethylated regions in proximity to ISGs.…”

Epigenetic modulation of myeloid cell functions in HIV and SARS-CoV-2 infection

“…after a mild SARS-CoV-2 infection) has been proposed to increase an individual’s susceptibility to the virus, which is paradoxically detrimental for the host. It is likely that these post-infection methylation patterns predict outcomes, possibly due to decreased viral suppression from down-regulated IFN activity [ 104 ]. In another independent study, the abundance of hyper- and hypomethylated sites in monocytes from convalescent COVID-19 patients was screened using epigenome-wide association studies (EWAS) [ 105 ].…”

The Initial COVID-19 Reliable Interactive DNA Methylation Markers and Biological Implications

“…The inclusion and exclusion criteria of the cohorts used in this study are the following: the sample sizes are larger than 20, and the numbers of CpG sites are matched by solving Equation (4). For clinical inclusion and exclusion criteria, readers are referred to the original study designs [3,14,32,33].…”

“…Four COVID-19 datasets to be analyzed in this study are publicly available: GSE174818 [14], GSE193879 [3], GSE179325 [32], and GSE219037 [33]. All four datasets used the same platform, GPL21145 Infinium MethylationEPIC, and about 865,859 methylation sites from whole blood samples.…”